Research in this program is focused on the basic mechanisms by which the host mobilizesand modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal systems for in vivo analysis. During infection and inflammation, leukocytes are recruited by chemokines from the circulation to inflamed tissues where they are activated by inflammatory mediators and matrix to stimulate T cells. Cell-specific chemokines are differentially expressed both spatially and temporally in inflamed sites. As the initiating agents are eliminated and inflammation wanes, the inflammatory cells are no longer necessary and must be removed from the tissues by apoptosis to resolve inflammation. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion with potential aberrancies underlies the development of strategies for modulating inflammatory diseases. In new studies, we have demonstrated that engagement of CTLA-4 on T cells induces TGF-beta production to mediate suppression and inhibit IFNgamma. Lack of TGF-beta is associated with overproduction of IFNgamma and uncontrolled inflammation. Downstream targets of IFNgamma include iNOS and transcription factors, NF-kappaB and IRF-1. Demonstration of elevated expression of NF-kappaB and IRF-1 in TGF-beta1 null mice supports the role of IFNgamma and downstream elements in the immune dysregulation displayed in the absence of TGF-beta1 and implicate TGF-beta1 as a key regulator of this pathway.